PROJECT SUMMARY/ABSTRACT Evident by the current trajectory in care cost for Alzheimer?s disease (AD), there is a critical need for decreasing the rate of incidence of AD. This goal can be accomplished through mitigating the impact of known risk-factors for AD. Treatments can be used to decrease or even halt progression to dementia, but only if we invest in research aimed at understanding the mechanisms contributing to the increased risk of AD after specific events. Among these events, compelling evidence indicates that traumatic brain injury (TBI) is a major risk factor for later development of Alzheimer?s disease, yet the mechanisms underscoring this increased risk are unknown. Understanding one putative mechanism linking TBI to increased risk of AD is the main scientific objective of the present research training project. Synaptic dysfunction is one of the primary events causing the initial cognitive decline in AD, and recent evidence has shown that toxic oligomers of both amyloid beta (A?) and tau interact and bind to the synapse and disrupt memory function through converging synergistic mechanisms. Furthermore, through its role in synaptic health and function, alterations in insulin sensitivity have been shown to increase vulnerability of the synapse to the binding and disruptive effects of amyloid oligomers. Notably, our lab has found acute alterations in insulin receptor (IR) activation after TBI. This project will investigate alterations in insulin responsiveness at the IR level and in downstream elements after TBI at more chronic time points using biochemical techniques. This suggests a mechanism through which incidence of TBI would increase the risk of developing AD through increased synaptic vulnerability to toxic AD proteinaceous species which will also be evaluated here using electrophysiology and flow cytometry. The extensive training that I will receive while completing this project will advance my knowledge in Alzheimer?s disease as well as traumatic brain injury. Completion of the training provided here will improve not only my research skills and experimental techniques but also my intellectually competency thereby preparing me for the next step in the pursuit of a future career as a PI at an academic institution.